BACKGROUND: The mineralocorticoid pathway is involved in cardiac arrhythmias associated with heart failure through mechanisms that are incompletely understood. Defective regulation of the cardiac ryanodine receptor (RyR) is an important cause of the initiation of arrhythmias. Here, we examined whether the aldosterone pathway might modulate RyR function. METHODS AND RESULTS: Using the whole-cell patch clamp method, we observed an increase in the occurrence of delayed afterdepolarizations during action potential recordings in isolated adult rat ventricular myocytes exposed for 48 hours to aldosterone 100 nmol/L, in freshly isolated myocytes from transgenic mice with human mineralocorticoid receptor expression in the heart, and in wild-type littermates treated with aldosterone. Sarcoplasmic reticulum Ca(2+) load and RyR expression were not altered; however, RyR activity, visualized in situ by confocal microscopy, was increased in all cells, as evidenced by an increased occurrence and redistribution to long-lasting and broader populations of spontaneous Ca(2+) sparks. These changes were associated with downregulation of FK506-binding proteins (FKBP12 and 12.6), regulatory proteins of the RyR macromolecular complex. CONCLUSIONS: We suggest that in addition to modulation of Ca(2+) influx, overstimulation of the cardiac mineralocorticoid pathway in the heart might be a major upstream factor for aberrant Ca(2+) release during diastole, which contributes to cardiac arrhythmia in heart failure.
BACKGROUND: The mineralocorticoid pathway is involved in cardiac arrhythmias associated with heart failure through mechanisms that are incompletely understood. Defective regulation of the cardiac ryanodine receptor (RyR) is an important cause of the initiation of arrhythmias. Here, we examined whether the aldosterone pathway might modulate RyR function. METHODS AND RESULTS: Using the whole-cell patch clamp method, we observed an increase in the occurrence of delayed afterdepolarizations during action potential recordings in isolated adult rat ventricular myocytes exposed for 48 hours to aldosterone 100 nmol/L, in freshly isolated myocytes from transgenic mice with humanmineralocorticoid receptor expression in the heart, and in wild-type littermates treated with aldosterone. Sarcoplasmic reticulum Ca(2+) load and RyR expression were not altered; however, RyR activity, visualized in situ by confocal microscopy, was increased in all cells, as evidenced by an increased occurrence and redistribution to long-lasting and broader populations of spontaneous Ca(2+) sparks. These changes were associated with downregulation of FK506-binding proteins (FKBP12 and 12.6), regulatory proteins of the RyR macromolecular complex. CONCLUSIONS: We suggest that in addition to modulation of Ca(2+) influx, overstimulation of the cardiac mineralocorticoid pathway in the heart might be a major upstream factor for aberrant Ca(2+) release during diastole, which contributes to cardiac arrhythmia in heart failure.
Authors: Cristian A Amador; Jean-Philippe Bertocchio; Gwennan Andre-Gregoire; Sandrine Placier; Jean-Paul Duong Van Huyen; Soumaya El Moghrabi; Stefan Berger; David G Warnock; Christos Chatziantoniou; Iris Z Jaffe; Philippe Rieu; Frederic Jaisser Journal: Kidney Int Date: 2016-02 Impact factor: 10.612
Authors: John C Gant; Kuey-Chu Chen; Christopher M Norris; Inga Kadish; Olivier Thibault; Eric M Blalock; Nada M Porter; Philip W Landfield Journal: J Neurosci Date: 2011-02-02 Impact factor: 6.167
Authors: Teresa M Seccia; Brasilina Caroccia; Gail K Adler; Giuseppe Maiolino; Maurizio Cesari; Gian Paolo Rossi Journal: Hypertension Date: 2017-04 Impact factor: 10.190
Authors: J C Gant; E M Blalock; K-C Chen; I Kadish; N M Porter; C M Norris; O Thibault; P W Landfield Journal: Eur J Pharmacol Date: 2013-11-28 Impact factor: 4.432